Does this patient have granulomatosis with polyangiitis (GPA)?

Granulomatosis with polyangiitis (Wegener's) (GPA) is a rare disease characterized by the presence of granulomatous inflammation and necrotizing vasculitis involving small and medium sized vessels in various organs.

Patients with GPA can have a variety of presentations based on the organ involved and severity of involvement.

Clinically, patients should be assessed as having severe (organ- or life-threatening manifestations) or non-severe (mild to moderate) disease.

It is more useful to use the terms, "non-severe" and "severe" disease, rather than the term, "limited GPA," (which was initially used to imply absence of renal involvement), as "limited" organ involvement can in itself be organ-threatening or life-threatening.

Common symptoms involve systemic features such as fatigue, fever, weight loss, night sweats, loss of appetite and nausea.

suspect sub-glottic stenosis in patients with or without a preceding diagnosis of GPA, who present with new onset hoarseness of voice or shortness of breath and a CT chest that does not reveal parenchymal disease

On some occasions, a typically non-severe manifestation such as lung nodules may be considered as severe in terms of decision making regarding therapeutic choices if there is extensive pulmonary involvement.

Patients with GPA are also at a higher risk of venous thrombosis, especially in the first 2-3 months of diagnosis when they are likely most debilitated from the illness and experiencing the most active phase of the disease. Patients with GPA who develop sudden shortness of breath, hypoxia, or leg swelling should be worked up for possible deep venous thrombosis/pulmonary thromboembolism.

What tests to perform?

Laboratory testing

Laboratory testing in patients with GPA (as in any other disease) should include tests that will provide information regarding diagnosis, disease severity, or for monitoring purposes (disease activity or medication toxicity).

Complete blood count with differential

Typical expected findings are leukocytosis (with a neutrophil predominance), anemia (normochromic normocytic) from anemic associated with chronic disease and possible blood loss (alveolar hemorrhage or other source) and normal or elevated platelet count. Leukopenia and thrombocytopenia are not primary features of GPA, and should raise suspicion for a secondary process or a different diagnosis.

Comprehensive metabolic panel

Urinalysis

This is an invaluable simple bedside test that can provide a clue to early renal involvement in GPA. Typically, the freshly obtained urine is tested by dipstick and then spun for microscopy if blood or white cells are detected. Presence of significant dysmorphic RBCs or RBC casts is indicative of glomerular disease. It is important to examine a fresh urine sample, as RBC casts tend to degenerate over time and may result in a false negative result.

Sedimentation rate and C-reactive protein

Both are generally elevated in the acute phase of the illness. However, although referred to as "markers of systemic inflammation," it is important to remember the non-specificity of both tests. There may also be a disconnect between these markers such an elevated ESR with a normal CRP (which can occur due to conditions such as polyclonal hypergammaglobulinemia). Elevations in ESR and CRP in patients deemed to be in remission deserve close follow up but do not in themselves merit change in therapy.

Anti-neutrophil cytoplasmic antibody (ANCA)

This test should be ordered in patients suspected to have GPA on clinical grounds (symptom complex listed earlier) and should be requested by both immunofluorescence (for pattern of ANCA) and enzyme immunoassay (for antigenic identification; typically proteinase-3 [PR3] or myeloperoxidase [MPO]). The combination of c-ANCA/anti-PR3 (~80%) or p-ANCA/anti-MPO (10-15%) has high specificity (>95%) for the diagnosis of GPA in the appropriate setting, but false positives do occur.

Other serologic testing, such as for infections, or tests for other suspected diagnoses are based on clinical suspicion for such illnesses. A litany of tests is not recommended and may result in false positive or inconclusive results that are unhelpful in management.

Imaging

Chest imaging is useful in detecting both asymptomatic and symptomatic pulmonary involvement from GPA. Lung nodules can often be silent if they are small and not compressing a major airway or are not near the chest wall where they may cause pleuritic chest pain. Alveolar hemorrhage can be asymptomatic if mild, and should be suspected in patients with the clinical trial of hypoxia, anemia, and a new infiltrate on chest imaging. CT chest without contrast is the preferable modality, as it is much more sensitive than chest x-ray at detecting pulmonary involvement from GPA. CT chest is also useful at detecting patterns that are suggestive of other diagnoses such as infection or malignancy.

GPA has been found to be associated with an increased incidence of venous thrombotic events. In patients suspected to have deep venous thromboses or pulmonary embolism, pertinent imaging, such as venous Doppler or CT chest, may be indicated.

Other testing may be driven by suspicion for alternative diagnoses, such as echocardiogram and blood cultures (for endocarditis), serum immunoglobulin measurement (for suspected immunodeficiency), serology for infections (such as fungal), sputum cultures and interferon-gamma release assay or Mantoux intradermal test (for tuberculosis), and other imaging based on organ involvement.

Bronchoalveolar lavage (BAL)

This may be indicated in patients with pulmonary manifestations of GPA, such as lung nodules or suspected diffuse alveolar hemorrhage, to confirm the diagnosis and, more commonly, to obtain samples (lavage fluid or biopsies) for excluding infection. Bronchoscopy is also extremely useful in assessing involvement and subsequent disease activity and offering local therapeutic intervention in patients with endobronchial involvement from GPA.

Biopsy

Tissue biopsy is useful in most situations for the diagnosis, but is equally helpful in excluding other diagnoses that can mimic GPA. Biopsies should be sought from involved organs and never blindly (from unaffected sites). Sinus biopsies and guided needle or transbronchial biopsies of the lung have low yield for diagnosis; open lung biopsy specimens and renal biopsies have the highest yield, although renal biopsies are generally not specific for GPA.

There is no pattern on histopathology that is pathognomonic of GPA. Both necrotizing granulomatous inflammation and features consistent with vasculitis (transmural infiltration with leukocytes, endothelial cell swelling, leukocytoclasia, thrombosis) may be observed in tissue specimens, but the presence of vasculitis is not a prerequisite for diagnosis, and granulomas are usually not seen on renal biopsies.

On lung biopsies, the pattern of necrosis is often referred to as "geographic" and may be surrounded by palisading histiocytes and giant cells. Other features on biopsy include neutrophilic microabscesses (collections of neutrophils with central necrosis), giant cells, epithelioid cells, non-necrotizing granulomas, venulitis, capillaritis, and collections of eosinophils. Less common accompanying features on histopathology of the lung include interstitial fibrosis, lipoid pneumonia, lymphoid aggregates, and bronchiolitis, including bronchiolitis obliterans.

Renal biopsy in GPA reveals a necrotizing crescentic glomerulonephritis with few/absent immune complexes on immunofluorescence or electron microscopy (referred to as "pauci-immune"). Interstitial inflammation or fibrosis may be also observed. If a medium sized vessel is present in the biopsy, it may show evidence of vasculitis in the form of transmural inflammation, fibrinoid necrosis, and luminal thrombosis.

Skin biopsies may show a pattern of leukocytoclastic vasculitis and, in themselves, are not useful for the specific diagnosis of GPA.

Diagnosis/Prognosis

The diagnosis of GPA is based on a combination of compatible clinical features, serology, and findings on tissue biopsy. The prognosis of patients with GPA depends on the severity of disease/organ involvement, specific organ involved, time to treatment, and choice of therapy.

Controversies

ANCA testing

The combination of c-ANCA/anti-PR3 (~80%) or p-ANCA/anti-MPO (10-15%) has high specificity (>95%) for the diagnosis of GPA. ANCA positivity in patients with GPA can vary depending on the population tested and disease expression. Up to 10% patients with GPA can be ANCA negative. Therefore, ANCA positivity is not a prerequisite for diagnosis.

The role of testing serial ANCA titers as a marker of disease activity is controversial and has been found to have weak predictive value in terms of determining subsequent disease relapse. Therefore, a rising ANCA titer (if serial testing is at all done) should not be grounds alone for escalating immunosuppression, but these patients may benefit from closer clinical follow-up to detect disease relapse early in this situation, allowing for timely intervention.

Chest imaging

As mentioned earlier, CT chest imaging (non-contrast) is a valuable tool to gain insights regarding disease activity from GPA involving the lungs, especially during asymptomatic relapses. However, there are no guidelines regarding the frequency of serial CT chest imaging in patients with GPA. Nonetheless, CT chest imaging should be considered in the assessment of disease activity in patients with GPA especially at time points where major changes in therapy are being contemplated (such as switching from induction to maintenance immunosuppression or reinstating induction therapy for a relapse of the disease).

Need for tissue biopsy

The need for biopsy may be obviated by the presence of strongly compatible clinical features accompanied by compatible positive ANCA serology with reasonable exclusion of infection or other diagnoses. However, biopsy is required in most cases to confirm the diagnosis, exclude other competing diagnoses and also to gain insight into disease severity.

How should patients with GPA be managed?

Treatment should be urgently instituted after confirming the diagnosis. In patients with severe organ-threatening or life-threatening manifestations, high dose glucocorticoids are used even while diagnostic confirmation is in progress in an attempt to control the severe inflammation early.

The treatment of GPA involves a two-stage approach: induction of remission and maintenance of remission.

Induction therapy includes high dose glucocorticoids (typically prednisone at 1 mg/kg/day with or without preceding intravenous methylprednisolone 1000 mg for 3 doses) and methotrexate (MTX) or rituximab (RTX) for non-severe disease and cyclophosphamide (CYC) or RTX for severe disease, respectively. Although there are few data to support the use of intravenous methyprednisolone as high dose glucocorticoid induction therapy, it is commonly used in patients with severe disease.

Untreated GPA has a very high mortality rate. Glucocorticoids form the cornerstone of treatment for GPA. However, it has clearly been shown that combination therapy with glucocorticoids and a second immunosuppressive agent from the beginning leads to more optimal outcomes in GPA. The choice of the second agent is determined by disease severity and experience of the clinician.

In the 1970s, the use of cyclophosphamide (CYC) and glucocorticoids represented a paradigm shift in the treatment of GPA. This combination led to significant improvement in the median life expectancy of patients with GPA. However, CYC administration, especially over extended periods, has significant toxicity and should be used only for a limited duration and for severe manifestations of GPA.

In 2010, the RAVE study in the United States and RITUXIVAS study from Europe compared rituximab (RTX) and CYC for induction of remission in patients with both GPA and microscopic polyangiitis (MPA). The study included patients with a new diagnosis of and relapsing GPA and MPA. In the RAVE trial, in patients with a new diagnosis of GPA/MPA, RTX was non-inferior to CYC in inducing remission, whereas in patients with relapsing disease, it was superior to CYC in inducing remission.

RTX was approved by the FDA in 2011 for the treatment of patients with GPA. However, the availability of RTX does not obviate the need for CYC use; CYC still has a potential role in the management of patients with severe GPA. A glucocorticoid taper is generally attempted after the first month on high dose glucocorticoid therapy.

In a post hoc analysis of the RAVE study, in patients with renal disease in both the CYC and RTX groups, no differences in remission rates or increases in GFR at 18 months were observed based on ANCA type, the diagnosis (GPA versus microscopic polyangiitis), or new diagnosis versus relapse at enrollment.

The route of administration of CYC is a matter of controversy in GPA. Daily CYC is administered at 2 mg/kg/day orally while intravenous CYC is given as 15 mg/kg every 2 weeks for the first three doses, every 3 weeks thereafter until remission, and then for another 3 months (CYCLOPS study protocol), usually for a maximum of 6 months. The maximum pulse dose allowed in the CYCLOPS study was 1.2 grams.

There was no difference in time to remission in the two groups or the proportion of patients in each group achieving remission. Although there was a difference in the relapse rates (13 patients in the IV versus six patients in the oral group), the study was not powered to detect these differences. In patients with non-severe disease, MTX in combination with high dose glucocorticoids is effective in inducing disease remission. MTX should be started at 15 mg/week and the dose increased to 20-25 mg/week (parenteral administration should be considered) over the next 2-4 weeks as tolerated. MTX is avoided in patients with renal dysfunction.

The role of plasma exchange (plasmapheresis) (PLEX) in the management of GPA is unclear. In patients with severe manifestations, such as rapidly progressive glomerulonephritis (RPGN) or diffuse alveolar hemorrhage that are resistant to standard induction therapy, plasmapheresis may have a role in achieving rapid control of inflammation.

In the MEPEX study, a randomized controlled trial (RCT) that included patients with both GPA and MPA with severe renal involvement (biopsy proven and creatinine > 5.8 mg/dL), the use of seven cycles of PLEX in addition to cyclophosphamide and oral prednisolone resulted in a greater proportion of patients being independent of dialysis at 3 months (primary outcome) compared to patients who received methylprednisolone 3000 mg. However, at one year follow-up, patient survival was comparable in the two groups.

There are no existing RCTs regarding the use of plasma exchange in patients with severe diffuse alveolar hemorrhage. An ongoing study, PEXIVAS (Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil antibody associated vasculitis: an international randomized controlled trial) may be able to provide further data regarding the role of PLEX in the management of patients with GPA. If there is a decision to use RTX as the induction agent, PLEX should precede RTX therapy, as RTX can be removed from the circulation by PLEX.

The induction period is typically 3-4 months but in the rare patient with smoldering disease activity, may extend to 6 months. Once the disease is deemed to be in remission at this time point, a switch is made from CYC to maintenance immunosuppressive therapy, such as methotrexate (MTX) or azathioprine (AZA) or mycophenolate mofetil (MMF). In patients who were on MTX to begin with, the MTX is continued with further tapering of glucocorticoid therapy.

The choice of a maintenance immunosuppression agent should be individualized based on factors such as comorbidities, personal preferences, and risk of medication toxicities. MTX would be relatively contraindicated in patients with hepatic or renal disease, whereas azathioprine would be contraindicated in patients who are homozygous recessive for the thiopurine methyltransferase (TPMT) gene (0.3% of the population) due to leukopenia. MMF is generally felt to be less effective than the others.

Following the effectiveness of RTX as an induction agent, there is growing interest regarding its role as a possible maintenance immunosuppressant in GPA. The French Vasculitis Study Group has published a randomized study (MAINRITSAN) of 115 patients with newly diagnosed or relapsing GPA, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis assigned to either RTX 500 mg on days 0 and 14 (induction) and at months 6, 12, and 18 after study entry or daily azathioprine until 22 months. Patients were followed until month 28. They reported a higher proportion of patients relapsing in the azathioprine group compared to the RTX group. In the US, a randomized controlled trial of RTX versus azathioprine (RITAZAREM) is presently underway (ClinicalTrials.gov Identifier: NCT01697267).

Intravenous abatacept (CTLA-4 Ig) has been recently studied in a small open label trial of 20 patients with non-severe relapsing GPA. Ninety percent of the patients experienced improvement in their disease condition and 80% experienced disease remission at median 1.9 months. Seventy three percent of the patient were able to completely discontinue prednisone use. Abatacept is presently not approved for the treatment of GPA and the results of this open label trial need to be confirmed in a larger randomized controlled trial of abatacept in patients with GPA. A randomized controlled trial of abatacept for relapsing, non-severe GPA is underway in the U.S. (ClinicalTrials.gov Identifier: NCT02108860).

All medications used for treating GPA are fraught with considerable toxicities that range from relatively benign such as nausea and vomiting to serious adverse effects such as severe infections and malignancies. Therefore, the need for clinical and laboratory monitoring in patients with GPA on immunosuppression cannot be overemphasized.

There are no formal guidelines for monitoring medication toxicity; however, some recommendations can be made. At minimum, patients should have complete blood counts (CBC), comprehensive metabolic panel, acute phase reactants (sedimentation rate and C-reactive protein) and urinalysis performed once a month while in remission and more frequently during the acute stage of the illness and while therapy is being adjusted.

Patients on CYC may develop hematologic toxicities such as significant leukopenia (defined in most studies as a WBC count <4000/mm3 and absolute neutrophil count <1500/mm3) from the cumulative effects of CYC being administered on a daily basis. In addition to the quantitative and qualitative effects of CYC on leukocytes, it should be borne in mind that these patients are on concomitant high dose glucocorticoids which compound the risk of severe infection.

Monitoring for leukopenia is imperfect as it does not assess functional aspects of leukocyte dysfunction; however, it is a cheap and possibly cost-effective means of preventing potentially severe infections. Weekly CBC monitoring in patients on CYC has been shown potentially cost-effective in preventing severe leukopenia and consequent infection in patients with GPA when compared with monthly CBC monitoring. In patients who do not have initial renal involvement, teaching weekly home urine dipstick testing may aid in early detection of relapses involving the kidney.

Patients with subglottic and endobronchial disease from GPA may require additional local therapeutic intervention within the airways with dilatation and injection of glucocorticoids and use of topical medications such as mitomycin C. Other local interventions may also be necessary for active disease as well as manifestations resulting from damage.

Patients with non-severe relapses of GPA following induction therapy with rituximab or cyclophosphamide benefit from the temporary use of a higher dose of glucocorticoids, but may need a change in background maintenance immunosuppression to stave off frequent relapses.

The importance of adjunctive prophylactic therapies cannot be overemphasized. In patients with GPA on high dose glucocorticoids and a second immunosuppressant (CYC, RTX, MTX, AZA or MMF), prophylaxis against Pneumocystis jirovecii (PJP)is of critical importance, as there is an increased risk of this infection that is associated with high mortality. The exact duration of PJP prophylaxis is unclear. Agents used for prophylaxis include trimethoprim-sulfamethoxazole, inhaled pentamidine, dapsone or atovaquone.

Since patients with GPA are also expected to be on glucocorticoids for extended periods of time, patients should be on calcium and vitamin D supplementation. Bone density testing using dual energy x-ray absorptiometry (DXA) should be performed in keeping with guidelines for osteoporosis. The use of antiresorptive therapies for prevention or treatment of osteoporosis should be instituted on an individual basis for these patients.

What happens to patients with GPA?

Timely treatment is vital in controlling inflammation in patients with GPA and preserving organ function. Patients should be followed closely (clinically, labs and imaging) after initiating immunosuppression to assess response to therapy. As patients are followed prospectively, it is extremely important to separate disease activity from inflammation versus organ damage in terms of making therapeutic decisions, as changing or escalating immunosuppression for damage is unnecessary and may even be harmful.

In clinical studies of patients with GPA, the Vasculitis Damage Index (VDI) is used to assess organ damage in target areas. For purposes of the VDI, damage is defined as having been present for at least 3 months and has occurred since the onset of vasculitis. Examples of damage in patients with GPA include persistent hematuria, neuropathic symptoms (motor or sensory), saddle nose deformity, subglottic stenosis, endobronchial scarring, and pulmonary fibrosis (can present as unchanging nodules on chest imaging). Renal transplantation is generally as successful as in other (non-diabetic) patients.

GPA tends to be a relapsing disease, and future relapses may involve previously involved or new areas. However, every attempt should be made to clarify the mechanism underlying the new symptoms before making changes in therapy. As most of these patients are immunosuppressed, infection should be high on the differential diagnoses in addition to other etiologies, such as disease relapse, malignancy (which can occur with long term immunosuppression), or organ damage from previous involvement from vasculitis. For example, a patient presenting with new shortness of breath may have underlying pneumonia, active vasculitis or damage (parenchymal involvement or subglottic stenosis or deep venous thrombosis in the lower extremities with pulmonary embolism).

It should also be borne in mind that certain manifestations of GPA ,such as subglottic stenosis and endobronchial disease, may be active despite disease activity in other areas being deemed as remission.

Glucocorticoids contribute to significant morbidity, including weight gain in patients with GPA with several short term toxicities (potentially reversible) such as weight gain, hypertension, glucocorticoid induced diabetes mellitus, and long term toxicities (potentially irreversible) such as osteoporosis or avascular necrosis of bone such as the femoral head. It is well appreciated that GPA has a significant impact on patients' quality of life as measured by the short form-36 (SF-36).

How to utilize team care?

Specialty consultations

Given the multi-organ involvement from GPA, it is extremely helpful to have the input and expertise of other specialists in the management of patients with GPA. Specialists commonly involved include Otolaryngology, Pulmonary, and Nephrology; however, other specialists may be consulted depending on the organ involvement in GPA. The expertise of a Vascular Medicine specialist may be required if patients are on anticoagulation for thrombotic complications of GPA.

Pharmacists

Patients with multiple comorbidities and subsequently on several medications with potential drug interactions may benefit from consultations with pharmacists to optimize compliance of therapy. Referral to a dedicated anticoagulation clinic may be required for patients on anti-thrombotic therapy such as warfarin.

Dietitians

Weight gain is the most common adverse effect experienced by patients on glucocorticoids. Dietary counseling may be very useful in planning healthy weight loss. Also, patients on therapies such as anticoagulants may need adjustment of diet to optimize requirement for warfarin dosing.

Physical therapy

Patients may benefit from referral to physical therapy for general deconditioning, fibromyalgia, pulmonary rehabilitation, healthy weight loss, and certain organ damage manifestations from GPA such as neuropathy.

Are there clinical practice guidelines to inform decision making?

Currently, no guidelines exist for the management of GPA.

Other considerations

Typical length of stay: For inpatients, the typical duration of admission may be 3-5 days for evaluation and initial treatment. For patients requiring intensive care, the stay is typically longer, especially if complicated by the disease itself or as a consequence of immunosuppressive therapy such as infection.